Anti-PEG antibodies compromise the integrity of PEGylated lipid-based nanoparticles via complement

补体系统 聚乙二醇化 化学 抗体 脂质体 经典补体途径 PEG比率 生物物理学 生物化学 细胞生物学 免疫学 生物 聚乙二醇 财务 经济
作者
Mariona Estapé Sentí,Caroline A. de Jongh,Kim Dijkxhoorn,J. Verhoef,János Szebeni,Gert Storm,C. Erik Hack,Raymond M. Schiffelers,Marcel H.A.M. Fens,Péter Boross
出处
期刊:Journal of Controlled Release [Elsevier BV]
卷期号:341: 475-486 被引量:115
标识
DOI:10.1016/j.jconrel.2021.11.042
摘要

PEGylation of lipid-based nanoparticles and other nanocarriers is widely used to increase their stability and plasma half-life. However, either pre-existing or de novo formed anti-PEG antibodies can induce hypersensitivity reactions and accelerated blood clearance through binding to the nanoparticle surfaces, leading to activation of the complement system. In this study, we investigated the consequences and mechanisms of complement activation by anti-PEG antibodies interacting with different types of PEGylated lipid-based nanoparticles. By using both liposomes loaded with different (model) drugs and LNPs loaded with mRNA, we demonstrate that complement activation triggered by anti-PEG antibodies can compromise the bilayer/surface integrity, leading to premature drug release or exposure of their mRNA contents to serum proteins. Anti-PEG antibodies also can induce deposition of complement fragments onto the surface of PEGylated lipid-based nanoparticles and induce the release of fluid phase complement activation products. The role of the different complement pathways activated by lipid-based nanoparticles was studied using deficient sera and/or inhibitory antibodies. We identified a major role for the classical complement pathway in the early activation events leading to the activation of C3. Our data also confirm the essential role of amplification of C3 activation by alternative pathway components in the lysis of liposomes. Finally, the levels of pre-existing anti-PEG IgM antibodies in plasma of healthy donors correlated with the degree of complement activation (fixation and lysis) induced upon exposure to PEGylated liposomes and mRNA-LNPs. Taken together, anti-PEG antibodies trigger complement activation by PEGylated lipid-based nanoparticles, which can potentially compromise their integrity, leading to premature drug release or cargo exposure to serum proteins.
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